To evaluate the usefulness of a novel acoustic uroflowmetry- (UFM-) based mobile application (app) voiding diary (VD) focusing on the (1) compliance and (2) correlation with a conventional paper-based VD.  A total of 78 patients were included between December 2019 and June 2020, and a subsequent review of all data was performed. The analyzed data were as follows: (1) survey of convenience/satisfaction/preference comparing the two methods, (2) compliance regarding the completeness of both methods, and (3) correlation of each metric  between the two methods. r = 0.55, p = 0.04), nocturnal polyuria index , total number of voids , number of nocturnal voids , and maximal bladder capacity .  The survey results of convenience, satisfaction, and preference were as follows. With regard to convenience and satisfaction area, higher scores are reported in the mobile app VD (mean ± standard deviation (SD); convenience: 7.47 ± 2.19 [app] vs. 4.20 ± 2.49 [paper]; satisfaction: 7.36 ± 2.17 [app] vs. 5.07 ± 2.65 [paper]). The median score of the overall preference for using the mobile app instead of the paper-based VD was 9 out of 10 (mean ± SD7.82 ± 2.68). We also found a good correlation between the two methods for nocturnal urine volume ( The acoustic UFM-based mobile app VD demonstrated favorable findings compared to the conventional paper-based VD. COVID-19 is extremely potent and contagious, and we are still feeling the great impact of the global COVID-19 pandemic . This puA VD is essential to evaluate both male and female LUTS patients . It contr] = 0.96). To the best of our knowledge, there are no other portable or mobile-based VDs that automatically record the voided volume. Previous smartphone-based VD apps were used only to facilitate patient fulfillment or improve compliance [In our previous study, we introduced a new smartphone-based uroflowmetry (UFM) device using acoustic analysis and reported results comparable to those of contemporary office-based UFM . Notablympliance , 12.Thus, we evaluated the usefulness of a novel acoustic UFM-based mobile app VD , which records voided volume automatically, by comparing it with a conventional paper-based VD in the current study. We specifically focused on (1) convenience/satisfaction/preference, (2) compliance, and (3) correlation between the two methods in male patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH).We performed this prospective comparative study after Institutional Review Board (IRB) approval from the Seoul National University Bundang Hospital  and in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments. We obtained informed consent from all patients who were enrolled in the study. Personal identifiers were completely removed, and the data were analyzed anonymously.The Healthy Bladder is a smartphone-based, automated VD. The app offers automated measurement using the built-in microphone of a smartphone rather than the void amounts in a standard measuring cup. When a patient urinates into a toilet bowl, the app captures ambient sounds generated by the event and the machine learning algorithm infers key voiding parameters from the acoustic signals. Lee et al.  conducteThe app was devised to alleviate the inconvenience and hassle of using a traditional measuring cup and a paper-based voiding diary. Furthermore, it is expected that the app would improve compliance with keeping a VD, guarantee the integrity of the data, and reduce potential recall bias of the patients.n = 5), were female (n = 5), did not complete both VDs (n = 13), or had no app-supported smartphone (n = 12). Finally, 78 patients with adequately recorded 3-day voiding diary by both methods were enrolled, and a subsequent review of all data was performed  survey of convenience/satisfaction/preference comparing the two methods, (2) compliance regarding the completeness of both methods, and (3) correlation of each metric  between the two methods.To eliminate recall bias, the patients completed a questionnaire at the end of each study. The three questions in the questionnaire were as follows: Q1: how convenient was the mobile app VD compared to the conventional paper-based VD (convenience)? Q2: how satisfied were you with the mobile app VD compared to the conventional paper-based VD (satisfaction)? Q3: do you prefer the mobile app VD to the conventional paper-based VD (preference)? The ratings for all three questions were separately self-reported on a scale of 0 (negative) to 10 (positive).t-tests and equal-variance tests were used to determine whether there was statistical evidence that the associated means and variances of the two methods, the conventional paper-based VD and the acoustic UFM-based mobile app VD, were significantly different. To validate the statistical characteristics of the voided volume from each method, independent t-tests and equal-variance tests were also chosen for the associated means and variances, respectively. The statistical analysis and calculations were performed using the Python™ v3.6.9 programming language and its scientific computing package SciPy v1.4.1 .Independent 2 , respectively. The median international prostate symptom score and overactive bladder symptom score were 13  and 4 , respectively. The median total prostate volume and transitional zone volume measured by transrectal ultrasonography was 32.0 mL  and 12.3 mL , respectively. The median prostate-specific antigen value was 0.951 ng/mL .A total of 78 male LUTS/BPH patients who completed both the conventional paper-based and acoustic UFM-based mobile app VDs for at least three days each were analyzed in the study. The median age and body mass index were 55.0 years  and 24.8 kg/mp < 0.05). In addition, among 78 patients, more than 85% (n = 67) completed more days on the VD app than the paper-based VD. In contrast, the VD app had fewer total voids recorded. However, the statistical characteristics of both methods were similar. This means that the difference was due to not only the technical differences between the two methods but also the intrinsic deviation of the statistic number of voids and/or voided volume , nocturnal polyuria index , total number of voids , number of nocturnal voids , and maximal bladder capacity  in 24 patients with good concordance . However, in these previous studies, apps were used only to facilitate patient fulfillment or improve compliance [Conventional paper-based VDs have several limitations including patient fulfillment/compliance and time-consuming interpretation of the data. Accordingly, electronic VDs designed to optimize compliance and effectiveness have been introduced. Compu-Void, a personal computer-based VD, was the first electronic VD model. Patients could use it after downloading programs onto a personal computer. Rabin et al.  found simpliance –14.To the best of our knowledge, our acoustic UFM-based mobile app VD was the first portable device recording voided volume automatically. In our previous study, we introduced a smartphone-based UFM device using acoustic analysis and reported a result comparable to that of contemporary office-based UFM . The resThe limitations include the interference of results with significant background noise. In addition, we only included male LUTS/BPH patients due to the gender differences in acoustic UFM techniques. Male patients have louder voiding sounds derived from the standing position, which has no barrier to noise reduction. Therefore, more sophisticated and separate methods are required for each gender. In addition, the voided volume recorded in the acoustic UFM-based mobile app VD was generally larger than that in the paper-based VD (Supplemental Figures The acoustic UFM-based mobile app VD demonstrated favorable findings in terms of convenience/satisfaction/preference and compliance and also showed reliable correlation with a conventional paper-based VD in male LUTS/BPH patients. Future large-scale prospective studies are needed to further validate our results.


However, these results were not consistent with the related changes in the expression of genes and/or proteins involved in protein synthesis or angiogenesis. Based on the results of previous studies, it seems certain that the expression at the molecular level does not represent the phenotypes of skeletal muscle and angiogenesis. This is because aging and long-term exercise are variables that can affect both protein synthesis and the expression patterns of angiogenesis-related genes and proteins. Therefore, in aging and exercise-related research, various physical fitness and angiogenesis variables and phenotypes should be analyzed. In conclusion, LSE appears to maintain the potential of angiogenesis and slow the aging process to maintain skeletal muscle mass and quality. Aerobic exercise may thus be effective for the prevention of sarcopenia.There has been an increasing awareness of sarcopenia, which is characterized by a concomitant decrease in skeletal muscle mass and quality due to aging. Resistance exercise is considered more effective than aerobic exercise in terms of therapeutic exercise. To confirm the effect of long-term aerobic exercise in preventing sarcopenia, we evaluated the skeletal muscle mass, quality, and angiogenic capacity of super-aged mice that had undergone lifelong spontaneous exercise (LSE) through various experiments. Our findings show that LSE could maintain skeletal muscle mass, quality, and fitness levels in super-aged mice. In addition,  Sarcopenia is a degenerative disease in which the mass, quality, and strength of skeletal muscles are lost due to aging ,2. SarcoMany studies aimed at improving sarcopenia have led to the development of biological mechanisms applicable to treatment and drugs targeting them . Most drAfter the onset of sarcopenia, resistance exercise is mainly recommended from a therapeutic point of view . Resistain vivo by changes in transcription and stability, protein synthesis and interactions with other growth factors [+-dependent histone deacetylase, to have a positive effect on maintaining vascular function and preventing aging of ECs [Regular endurance exercise is known to maintain energy homeostasis and delay senescence and premature death . In addi factors . The fun factors . However factors . It is b factors –22. The  factors ,24. Howeg of ECs ,26. In ag of ECs .Nevertheless, the effect of endurance exercise on sarcopenia is underestimated compared to that of resistance exercise. The reason for this is that the studies so far have mainly focused on therapeutic approaches after the onset of sarcopenia. In addition, large-scale epidemiological studies are difficult to control for variables that directly or indirectly affect endurance exercise. In the case of clinical studies, it is difficult to obtain various physiological phenotypes in the muscles following endurance exercise through research because long-term endurance exercise intervention over a lifetime is virtually impossible.Our previous study indirectly demonstrated that the risk of premature death can be lowered by maintaining energy homeostasis in super-aged mice subjected to lifelong spontaneous exercise (LSE) . TherefoWe aimed to investigate the quantity and quality of skeletal muscle in 25-month-old super-aged mice  , which cad libitum, which were replaced with fresh feed and water daily. All mice were euthanized after being deeply anesthetized with isoflurane. The intervention method in this study was not an experiment that caused pain in mice. For the welfare of the mice, new feed and drinking water were provided at least twice a week. In addition, the bedding was changed at least once a week to maintain a comfortable environment. All procedures involving animals were in accordance with the ethical standards of the Institutional Animal Care and Use and Committee of Pusan National University .Experiments were performed at the Animal Care Facility of The Pusan National University School of Medicine in Yangsan, Gyeongsangnam-do. Female C57BL/6 mice  were purchased from Samtako . All mice were housed in a room maintained at 22–24°C, with 50–60% relative humidity, under a 12 h light/12 h dark cycle. The mice were supplied with a normal diet  and fresh water n = 7) and the remaining half were bred in cages without a wheel . To perform the aging study, mice were maintained until 25 months of age (99 week old). For comparison with the aging study, 6-week-old young mice were bred for 16 weeks in the same manner as the mice used in the aging study . To exclude the immediate physiological effects on the experimental animals, the spontaneous wheels were removed from the cages of the Young-EXE and Old-EXE groups 48 h before sacrifice. At the end of the aging study, young mice were simultaneously euthanized at 22 weeks of age .The overall design of this study was described in our previous study . After pWe reviewed the results of a physical fitness test published in our previous study to identify the level of fitness that is highly related to skeletal muscle loss and aging . The dat® Lysis Reagent  and placed in a microfuge tube. The eluate contained in the microfuge tube corresponds to ECs. The iliac artery tissue after the lumen was flushed corresponded to the smooth muscle cells (SMCs). The carotid artery was used for western blotting and aortic ring assay. After blood vessel sampling, the gastrocnemius muscle was collected. After peeling off the skin and fascia sequentially from the hind limb of the euthanized mice, the Achilles tendon was cut with scissors, and the gastrocnemius muscle was separated by lifting it with forceps. Red gastrocnemius was removed from collected gastrocnemius, and only white gastrocnemius was sampled. Muscle samples were freshly weighed on an Adventurer™ micro-analytical scale immediately after dissection.After anesthesia using isoflurane, the body weights of the experimental animals were measured on an Adventurer™ micro-analytical scale . Then, the skin was incised from the lower abdomen to the sternal region, and the rib cage was opened. The full-length aorta extending 5–10 mm below the bifurcation of the iliac artery, including the subclavian right and left common carotid arteries, was removed. The excised full-length aorta was cut into the carotid and iliac arteries. The iliac artery was then quickly flushed (few seconds) using a 29-gauge insulin syringe containing QIAzolTM for Cell/Tissue . Proteins from the carotid artery were extracted the same way as the gastrocnemius and used for western blotting of angiogenesis-related proteins (VEGF and VEGFR2). The protein extracts were separated by 12% SDS-polyacrylamide gel electrophoresis and transferred to polyvinylidene difluoride (PVDF) membranes . The membranes were blocked in 5% (w/v) non-fat dry milk for 1 h and incubated with primary antibodies overnight at 4°C. The primary antibodies used were as follows: anti-glyceraldehyde 3-phosphate dehydrogenase (GAPDH) antibody , anti-mTOR antibody , anti-IGF1 antibody , anti- ribosomal protein S6 kinase beta-1 (S6K1) antibody , anti-beta actin antibody , anti-VEGF antibody  and anti-VEGFR2 antibody . The membranes were then incubated for 1 h at room temperature with horseradish peroxidase-conjugated secondary antibodies (suitable for each primary antibody): goat anti-rabbit  or goat anti-mouse  secondary antibodies.The gastrocnemius muscle, which is known to suffer the greatest loss due to aging among the skeletal muscles, was collected after sacrifice of mice and stored in a deep freezer below -80°C. The gastrocnemius muscle was used to the white gastrocnemius, which has a relatively high proportion of type II muscle fibers compared to the red gastrocnemius . Frozen Hematoxylin & eosin staining was performed to determine the fiber CSA. A paraffin-embedded block was fabricated using the gastrocnemius muscle fixed with 4% paraformaldehyde. The paraffin-embedded block was cut into slices with a thickness of 5 μm using a microtome, and the sections were placed on a glass slide. Paraffin-embedded sections were deparaffinized, hydrated, and stained with hematoxylin for 5 min. The sections were rinsed with tap water for 10 min. The sections were then decolorized using 1% HCl, rinsed with tap water for 10 min, stained with eosin for 1 min, and dehydrated in gradient alcohol. The sections were then cleared in xylene prior to sealing with neutral gum. For CSA analysis, 20 non-overlapping representative fields of the muscle tissue of each mouse were imaged under a light microscope using a 20 × magnification , and the CSA was measured using image analysis software .® RT Premix  according to the manufacturer’s instructions. The cDNA was mixed with forward and reverse primers for qPCR in a 384-well plate  containing Power SYBR® Green PCR Master Mix .After sacrificing the mice, ECs and SMCs stored in a deep freezer at -80°C were homogenized. All samples were homogenized using an ultrasonicator . Total RNA was isolated using TRIzol reagent , and cDNA was synthesized from the RNA using AccuPowerPecam1 and Acta2 were selected to differentiate between EC (Pecam1 expression > Acta2 expression) and SMC (Acta2 expression > Pecam1 expression). In addition, angiogenesis-related genes were analyzed in ECs and SMCs in triplicate. To normalize the mRNA levels among samples, Gapdh was amplified by qPCR as a housekeeping gene. The reaction was performed using the ViiA 7 real-time PCR system (Applied Biosystems). Primer sequences used in the experiments are listed in ex vivo aortic ring assay was performed using the carotid artery w [TM-2 Endothelial Cell Growth Medium-2 BulletKitTM, #CC-3162, Lonza, Basel, Switzerland) pre-warmed in a water bath at 37°C. The carotid artery in the sample tube was divided into six equal rings (thickness ± 15 μm) in a petri dish. Fifteen minutes before the carotid artery ring was divided, Matrigel® Matrix  was dispensed on the bottom of the 24-well plate and placed in an incubator (37°C) to allow polymerization. The prepared carotid artery ring was implanted in the Matrigel® Matrix  to form an annular shape when viewed from above. Finally, cell growth media were added to each well and cultured in an incubator . After one week of culture, the number of branches protruding from the aortic ring was counted using a cell imaging system .To determine the angiogenic capacity, an artery w . The car2) in cell growth media . The HUVECs were fed every 2–3 days and sub-cultured once they reached 70–80% confluence. HUVECs passaged up to nine times were isolated from the cell culture dish with trypsin. The isolated HUVECs were plated in a cell culture dish (3 × 106 cells) for the wound-healing assay. Out of a total of 15 cell culture dishes, 5 dishes were subjected to LSS on a shaker (20 dyne/cm2), 5 dishes were treated with H2O2 (100 μM/L) to induce OS, and 5 dishes were subjected to LSS and treated with H2O2 simultaneously; the rest of the dishes were used as controls. LSS was treated on a shaker for 24 h, then H2O2 was added, and the wound-healing assay was performed 1 h later. A single scratch was made on the endothelial monolayer of the cell culture dish using a micropipette tip. Subsequently, the cells were washed once with phosphate-buffered saline and cultured under the same conditions. The surface of all scratches (10 Ⅹ magnification) was observed using a cell imaging system  at 0 h and 9 h of culture. Migratory distance was measured using the ImageJ program .To indirectly determine the effect of senescence and aerobic exercise on the regenerative capacity of blood vessels, scratch wound-healing assays were performed after applying LSS and OS to human umbilical vein ECs . HUVECs were maintained in a humidified atmosphere . After 9 h, cell tube formation (10 Ⅹ magnification) was captured using a cell imaging system . The number of branch points, total tube lengths, and tube formation areas were measured [A tube formation assay was performed to indirectly determine the effect of aging and aerobic exercise on angiogenic capacity. All culture conditions were the same as those used in the wound healing assay. In addition, LSS application and Hmeasured  in the cex vivo aortic ring assay were statistically analyzed by two-way ANOVA and Sidak’s post hoc test. The results of the scratch wound-healing assay and tube formation assay were statistically analyzed by one-way ANOVA Tukey’s post hoc test. All statistical analyses were performed using the GraphPad Prism ver. 8 . Statistical significance was set at p < 0.05.The results obtained by the physical fitness test, western blotting, qPCR, and p < 0.0001), significantly longer in Young-EXE than in Young-CON mice (p < 0.001), and significantly longer in Old-EXE than in Old-CON mice (p < 0.001) (p < 0.0001); however, the Old-EXE group spent a longer time on the rotarod than the Old-CON group (p < 0.05) (p < 0.0001), and Old-EXE mice had a higher score than the Old-CON mice (p < 0.05) (p < 0.0001). Additionally, both the Young-EXE (p < 0.05) and Old-EXE (p < 0.0001) groups demonstrated significantly longer spontaneous running distances than the control groups of the same age  . In the  < 0.05) . In the  < 0.05) . The sposame age .p < 0.05; gastrocnemius muscle, p < 0.001; soleus muscle, p < 0.01; extensor digitorum longus (EDL) muscle, p < 0.01; tibialis anterior muscle, p < 0.001) was significantly lower in the Old-CON than in the Young-CON group (p < 0.05) but significantly lower in Old-EXE than in Old-CON mice (p < 0.0001)  . All skep < 0.05). There was no significant difference in cross-sectional area between the other groups , and there was no significant difference between the other groups (The expression of insulin like growth factor 1 (IGF-1) and S6K1 was significantly lower in Young-EXE than in Young-CON mice . In SMC, Acta2 expression was significantly higher than Pecam1 expression (p < 0.001) (Vegfa and Vegfb expression was significantly higher in Young-EXE than in Young-CON mice (p < 0.0001) and in Old-CON than in Young-CON mice   and significantly lower in Old-EXE than in Old-CON mice (p < 0.0001) (Fgf1 expression was significantly lower in Old-CON than in Young-CON mice (p < 0.01) (Fgf2 expression was lower in Old-CON than in Young-CON mice (p < 0.001) and significantly higher in the exercise group  than in the control group of the same age  (Hgf expression was significantly lower in Old-CON than in Young-CON mice (p < 0.05) (Jmjd1a expression was significantly higher in Old-EXE than in Old-CON mice (p < 0.01)  . Therefo 0.0001) . Vegfc le groups . Plgf ex 0.0001) . Fgf1 ex < 0.01) . Fgf2 exsame age . Tsp1 ane groups . Ang1 an 0.0001) . Hgf exp < 0.05) . Jmjd1a  < 0.01) . In the  < 0.01) .p < 0.05) and significantly lower in Old-EXE than in Old-CON mice (p < 0.01). In addition, the VEGF expression in Old-CON was significantly higher than that in Young-CON mice (p < 0.001) (p < 0.05) and in Old-EXE than in Old-CON mice (p < 0.01) , by western blotting . VEGF ex< 0.001) . VEGFR2  < 0.01) .ex vivo aortic ring assay (p < 0.0001). In addition, it was confirmed that the exercise group  had higher angiogenic capacity than the control group of the same age , LSS conditions (p < 0.01) and LSS+OS conditions (p < 0.001) (p < 0.05)  and were significantly higher in LSS+OS conditions than in OS conditions   . Accordi< 0.001) , the num < 0.05) . All ite < 0.05) .Our present study demonstrates that lifelong spontaneous wheel running in experimental animals mimicking sustained human aerobic exercise can help alleviate the overall sarcopenia. It was shown that the decrease in skeletal muscle of the whole body due to aging can be largely offset by LSE. This was confirmed by the grip strength , relativIn our study, which confirmed that the mTOR signaling pathway is involved in both aging and protein synthesis, aerobic exercise in aged mice caused no difference in the expression of all the related proteins . HoweverVegfa, Vegfb, Plgf, Ang1, and Ang2)  showed that the angiogenic capacity decreased with aging and that exercise could offset the decrease in angiogenesis caused by aging. In particular, in the ex vivo aortic ring assay, blood vessels from experimental animals were extracted and cultured. Therefore, the aortic ring assay is the most definitive study to confirm whether the mice subjected to LSE maintain the angiogenic capacity. The aortic ring assay indicated that the angiogenic capacity of blood vessels was lower in aged mice than in young mice, but regardless of age, the exercise group had higher angiogenic capacity than the control group, suggesting that exercise maintains or protects the angiogenic capacity   . These r Old-EXE . In addiand Fgf2 . If onlyn occurs . Therefocapacity . We belicapacity . The stucapacity . It was capacity . It was capacity . Therefocapacity . An addiOS) Figs  and 9.This study showed that protein synthesis and angiogenesis-related genes and proteins must be analyzed together with physical fitness and various phenotypes to analyze the effect of aging and exercise. Taken together, our results show that the quantity and quality of skeletal muscles are maintained by delaying aging due to lifelong spontaneous aerobic exercise and maintaining the function of angiogenesis. These features appear to be independent of the synthesis of proteins involved in skeletal muscle growth.In conclusion, lifelong aerobic exercise is an excellent way to prevent sarcopenia by maintaining the angiogenic capacity, mass, and quality of skeletal muscles. However, aging and prolonged exercise can affect the expression of genes and proteins related to protein synthesis and angiogenesis. Therefore, in aging and exercise-related studies, it is necessary to prevent distorted interpretation through analysis of physical fitness test and various phenotypes rather than relying on results at the molecular level.S1 FigPecam1 vs. Acta2, ***p < 0.001.All data are presented as the mean ± SD. (TIFF)Click here for additional data file.S2 FigVegfa expression level. (B) Vegfb expression level. (C) Vegfc expression level. (D) Plgf expression level. (E) Fgf1 expression level. (F) Fgf2 expression level. (G) Tsp1 expression level. (H) Tsp2 expression level. (I) Ang1 expression level. (J) Ang2 expression level. (K) Hgf expression level. (L) Jmjd1a expression level. All data are presented as the mean ± SD. N. S. = no significant difference between groups.(A) (TIF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S1 Raw images(PDF)Click here for additional data file.


Despite the ongoing technical developments in imaging-based dosimetry, the existence of tumour absorbed dose-efficacy and organ absorbed dose-toxicity relationships, as well as the high interpatient variability in absorbed doses per unit activity, radiopharmaceutical therapies are still mostly administered in a fixed-activity, one-size-fits-all fashion. This is at odds with the principles of radiation oncology, where the absorbed doses to tissues are prescribed and their delivery is carefully planned and controlled for each individual patient to maximise the clinical benefits. There is a growing body of clinical evidence that dosimetry-based radiopharmaceutical therapy allows to safely optimise tumour irradiation, which translates into improved clinical outcomes. In this narrative review, we will present the reported prospective clinical experience to date on the use of imaging-based dosimetry to personalise radiopharmaceutical therapies.Theranostics – i.e., the combination of molecular imaging and radiopharmaceutical therapy of cancer targeting a common biological feature – is a rapidly expanding field owing the recent successes of novel radiopharmaceutical therapies, such as  For this, RPT distinguishes itself from most other cancer drugs , which are often given blind to disease- or patient-specific information. Exceptions include patient selection based on, e.g., germline genetic testing (e.g. BRCA mutations for poly(ADP-ribose) polymerase inhibitors) or histopathological features obtained from single-lesion biopsy, but such results provide little information on how effectively each lesion will be targeted by the drug, particularly in the setting of an heterogeneous metastatic disease.Radiopharmaceutical therapy (RPT) is currently revolutionising oncological care. It consists in the administration of particle-emitting radiopharmaceuticals that are designed to specifically target the cancer lesions while sparing, as much as possible, healthy tissues. The goal of RPT is to deliver a substantial amount of radiation to the tumour to cure it or, failing that, to achieve prolonged disease control and symptomatic palliation. Most RPT applications fall under the paradigm of internal  and targeted via a specific biological or mechanical pathway. The quantity of radioactivity administered is measured in becquerels , whereas the absorbed dose (to which “dose” refers to in this text) is the concentration of energy deposited in tissues expressed in grays (Gy). In radiotherapy, it is the absorbed dose, fractionation, type of radiation, and the dose rate that drive the biological effects, and these variables can be integrated to some extent into metrics of biological effectiveness .Another aspect making RPT standing apart from other systemic modalities is that its active ingredient is not the pharmaceutical molecule itself, but the ionising radiation and consequent reactive oxygen species that are formed in situ following each decay, as well as direct DNA damage. Accordingly, RPT is a radiotherapeutic modality that is 32P to treat leukaemia and of 131I to treat thyroid cancer. Until the turn of the century, the practice of RPT has remained limited both in terms of RPTs available and number of patients treated. However, owing to the recent successes of a new generation of 177Lu-based RPTs, namely peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumours and prostate-specific membrane antigen radioligand therapy (PSMA-RLT) of prostate cancer, the field of theranostics is now developing at an accelerated pace and transforming the practice of nuclear medicine [131I RPT of metastatic thyroid cancer, has been adopted for 177Lu RPTs as a convenient one-size-fits-all portion with little dosimetry rationale. This approach ignores a founding principle of radiotherapy, which is to control and standardise the delivery of radiation to tissues, i.e. absorbed doses, as opposed to administered activity. Because the specific absorbed doses  are highly variable across patients for any healthy organ , and even more so for tumours (by at least two orders of magnitude), a fixed-activity treatment is unlikely to be optimal for all. And when an empiric RPT regime is tuned towards good tolerability, this will translate into the majority of patients being undertreated, i.e. receiving less radioactivity thus less tumour irradiation than they could realistically tolerate, with the consequent risk of suboptimal outcomes. In this respect, RPT is lagging far behind external radiation therapy, where the treatments are carefully tailored to each patient’s needs.RPT was born about 80 years ago with the introduction of There is a growing body of evidence supporting the personalisation of RPT based on individualised dosimetry. In this narrative review, we will summarise the current clinical experience with imaged-based dosimetry-guided protocols by highlighting the results of prospective clinical trials that are setting the bases of personalised RPT regimes. Key features and results of presented studies are compiled in Table 90Y glass microsphere radioembolisation in 60 patients with hepatocellular carcinoma. The treatment planning is done using pre-treatment angiography and 99mTc macroaggregated albumin (as the diagnostic surrogate tracer) planar and SPECT/CT scans to determine the volume of perfused liver and lung shunt (to limit the lung dose to 30 Gy). In the standard regime, the activity is prescribed with the assumption that it will distribute uniformly within the perfused liver volume, a worse-case scenario, with a limit of 150 Gy (target of 120 Gy) to that volume. However, this conservative approach ignores a fundamental principle of radioembolisation, i.e. that the arterial hepatic blood flow preferentially feeds the hypervascularised tumours rather than the normal liver parenchyma, which is perfused mostly by the portal vein. Accordingly, higher tumour sequestration of activity will inevitably reduce the dose to the normal liver by virtue of a sink effect. In the personalised arm, the activity prescription was escalated to deliver at least 205 Gy (target of 250 Gy) to the index tumour lesion, while not exceeding 120 Gy to the normal perfused liver parenchyma.Intra-arterial administration of radiolabelled microspheres, i.e. radioembolisation, is a loco-regional modality used in the management of liver malignancy. While it can be applied to treat metastatic liver lesions such as those from colorectal cancer or neuroendocrine tumours, it has primarily been developed as a modality against inoperable primary liver cancer. Benefits of a dosimetry-based approach in radioembolisation have been clearly shown by a French group led by Garin . The DOSp = 0.0049). There was a significant increase in objective response rate (ORR) of the index lesion (which was a lesion ≥7 cm) among the 28 evaluable patients in each group: 71% in the personalised group vs. 36% in the standard group (p = 0.0074). This constituted a statistically positive result for the primary endpoint at the interim analysis, so the trial was stopped. As a secondary endpoint, a significant difference in the median overall survival (OS) was found: 26.6 (95% CI: 11.7 – NR) mo. vs. 10.7 (95% CI: 6.0–16.8) mo., respectively . Progression-free survival (PFS) was not statistically different between groups . In the safety analysis, at least one serious adverse event was reported in 20% and 33% of patients receiving the personalised and the standard treatments, respectively, suggesting that the personalised treatment is as well tolerated as the standard approach despite the higher administered activity. Excluding lymphopenia, grade 3 or more adverse events were mostly of hepatic or gastrointestinal nature. One treatment-related death was recorded in each group. The DOSISPHERE-01 trial results probably represent to date the most compelling evidence of the superiority of a dosimetry-based regime over an empiric one.The prescribed median activity was significantly greater in the personalised group as compared with the standard group , was developed as an imaging dosimetry-based RPT for patients with non-Hodgkin lymphoma. An absorbed dose escalation study was conducted and 0.75 Gy to the whole-body was found to be the maximum tolerated dose [131I-tositumomab [3) based on pre-treatment dosimetry study using a diagnostic amount of 185 MBq 131I-tositumomab and 3-timepoint whole-body planar scan , to deduce the monoexponential clearance [131I-tositumomab in the bloodstream, allowing for greater tumour accumulation. Among the 250 patients, any response and a complete response (CR) were seen in 56%  and 30%  of patients, respectively, and the overall median PFS was 6.4 mo., with 32% of patients achieving a durable response (> 12 mo.). The median durations of any and complete responses were 12.9 and 58.4 mo., respectively. The toxicity was not included in this integrated analysis. In the latter of the five trials, grade 3–4 hematologic and non-hematologic toxicities were seen in 50 and 16% of patients, respectively, while 9% developed hypothyroidism  [131I-tositumomab through an expanded access program, 35 patients  developed myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML), among whom the diagnosis was independently confirmed in 23 patients  [Radioimmunotherapy of lymphoma using an anti-CD20 radiopharmaceutical, ted dose . The dat131I-tositumomab RPT in 76 treatment-naïve patients with stage III-IV follicular lymphoma, 95% of patients had an objective response and 75% had a CR [131I-tositumomab radioimmunotherapy thus appeared substantially more effective and better tolerated in treatment-naïve as opposed to heavily pre-treated patients. The subsequent clinical trials of 131I-tositumomab were based on a whole-body dose prescription in a non-myeloablative context, and, for some myeloablative protocols, on critical solid organ dosimetry (with autologous stem cell rescue). They are not fully reviewed here.In a subsequent trial of had a CR . The med131I-tositumomab, the anti-CD20 radioimmunotherapy with 90Y-ibritumomab  has been approved with a weight-based activity prescription (14.6 MBq/kg). As with the former, there is a pre-treatment imaging study, but without mandated dosimetry. The purpose of the pre-treatment diagnostic imaging with 111In-ibritumomab is limited to qualitatively ruling out an altered biodistribution. Like 131I-tositumomab, there is a cold antibody infusion – using rituximab in this case – immediately before each of the administrations of the diagnostic and of the therapeutic radiopharmaceuticals, 1 week apart. The rationale for weight-based prescription is related to the short physical half-life of 90Y (2.7 days) which becomes the dominant determinant of the effective whole-body half-life because the biological half-life of 90Y-ibritumomab is much longer. Consequently, the whole-body dose will be roughly proportional to the injected activity per body weight. Conversely,131I-tositumomab has a shorter and variable biological half-life paired with a long physical half-life, resulting in high inter-patient variability in whole-body specific absorbed dose [90Y-ibritumomab.Contrary to bed dose . The wei90Y-ibritumomab has also been studied as a myeloablative treatment in an image dosimetry-guided application. In this more invasive therapeutic approach involving autologous stem cells rescue, sparing the bone marrow and the spleen is not an aim. Rather, the critical dose-limiting organ becomes the liver. In a phase 1, absorbed dose escalation study, 18 patients with relapse or refractory follicular lymphoma who underwent a successful stem cell harvest  proceeded with a high-dose 90Y-ibritumomab radioimmunotherapy. Apart from first three patients who received the standard activity of 14.8 MBq/kg, 15 patients received a personalised activity to deliver 18 Gy (n = 5), 24 Gy (6), 28 Gy (3) or 30.5 Gy (1) to the liver. The hybrid pre-treatment dosimetry with 111In-ibritumomab consisted in 5-timepoint whole-body planar scan  plus a 2-bed SPECT/CT at 24 h to allow the scaling of the time-activity curve. Contrary to what is expected for the whole-body specific absorbed dose with 90Y-ibritumomab, there was a large inter-patient variability in the liver specific absorbed dose . There was grade 3–4 hematologic toxicity in most cases, as expected. There was not, however, any case of significant hepatic toxicity, suggesting that the liver maximum tolerated dose would be more than 28 Gy, which is supported by the 90Y radioembolisation data. Two patients who received 90Y-ibritumomab died from disease progression, and another one from pneumonia, while one patient developed MDS. Efficacy results were encouraging, with 16 patients achieving any response, 14 of whom, a CR. Median PFS was 13 mo., but highly variable (range: 0.1–40 mo.), and it was not possible to see any trend for the response rates or the PFS among the small patient cohorts with escalating liver doses. Another example of liver absorbed dose escalation study could be found in a myeloablative strategy against multiple myeloma, with 90Y-ibritumomab given as an adjunct to high-dose melphalan [However, elphalan . In cont153Sm-ethylenediaminetetramethylene phosphonic acid (EDTMP) is a phosphonate-based bone seeking agent while 89Sr chloride, another beta emitter, is a calcium analogue, as is the more recently introduced alpha emitter 223Ra chloride. It is noteworthy to highlight that 223Ra has been shown to prolong OS in patients with metastatic castration-resistant prostate cancer, but the study was conducted before the introduction of novel anti-androgen drugs [153Sm-EDTMP; 148 MBq or 1.5–2.2 MBq/kg for 89Sr; 55 kBq/kg for 223Ra) [153Sm-EDTMP regime has been developed by the group of Turner et al. from Australia [153Sm-EDTMP followed by 2-timepoint whole-body planar scans  to quantify whole-body activity retention which was assumed to be entirely in the bone, and this was used to compute the bone marrow absorbed dose. The resulting estimates correlated strongly with those derived from urine measurements, and the novel imaging-based method thus appeared as a more practical alternative. The therapeutic injection was done later the same day with a personalised activity to deliver 2 Gy to the bone marrow. There was no hematologic toxicity. Eight patients (80%) responded with complete (60%) or partial (20%) pain relief. The authors compared the bone marrow absorbed dose (1.97–2.07 Gy) with that which would have been delivered with the standard weight-based activity of 37 MBq/kg (3.27–5.90 Gy). Based on this, they extrapolated that the personalised approach may have prevented significant hematologic toxicity. However, in a large, randomised trial of 153Sm-EDTMP in which 37 MBq/kg was used, the rates of grade 3 thrombopenia and leukopenia remained modest at 3 and 5%, respectively [RPT with bone-seeking radiopharmaceuticals can effectively relieve bone pain in patients with bone metastases that are positive on bone scan. en drugs . The thrr 223Ra) –23. An iustralia . Initialectively .131I-metaiodobenzylguanidine (MIBG), a radiolabelled amine precursor, has been used to image  and treat pheochromocytoma, paraganglioma, neuroblastoma and some other neuroendocrine tumours such as those from the midgut. Using high-specific activity MIBG, a high-activity regime was studied in a multicentre, single-arm clinical trial in which 68 patients with pheochromocytoma or paraganglioma suffering from secondary hypertension were registered [131I-MIBG. The activity was adjusted per body weight in patients < 62,5 kg (296 MBq/kg), and personalised based on a pre-treatment dosimetry study consisting in the injection of 185 MBq 131I-MIBG and 3-timepoint whole-body planar scanning . There was an activity reduction in cases where pre-treatment dosimetry indicated that the fixed or weight-based activity would predict excessive absorbed dose to the bone marrow (> 12 Gy), lungs (> 16.5 Gy), kidneys (> 18 Gy), liver (> 31 Gy), or small intestine (> 40 Gy), as per the package insert [gistered . The rege insert . The choe insert , 26. Mor177Lu-DOTATATE consists in 4 cycles of 7.4 GBq given at 2-monthly intervals. In their 2008 report, the Rotterdam group retrospectively justified this regime based on their 2001 dosimetry data from only 5 patients: a cumulative activity of 29.6 GBq would result in a bone marrow dose not exceeding 2 Gy [177Lu-DOTATATE (Lutathera®) many years later [177Lu-DOTATATE plus standard dose of long-acting octreotide vs. high dose of long-acting octreotide. The primary endpoint of PFS was met, as 177Lu-DOTATATE prolonged PFS by 20 mo., from a median of 8.4 mo. in the control group to 28.4 mo. in the 177Lu-DOTATATE group [177Lu-DOTATATE vs. 36.3 mo. for the control group, and although clinically impressive, this difference did not reach the prespecified level of statistical significance [177Lu-DOTATATE, combined with the high interpatient variability in renal and bone marrow specific absorbed doses suggest that the majority of patients could tolerate a higher injected activity to increase tumour dose and clinical benefits. Below is summarised the experience of the three groups who reported on dosimetry-based personalised PRRT with 177Lu-DOTATATE.The current empiric fixed-activity regime of ing 2 Gy , 28. Thi177Lu-DOTATATE at 6 to 8-weekly intervals until a cumulative renal absorbed dose of 23 Gy or a bone marrow dose of 2 Gy was achieved. Kidney dosimetry was assessed using SPECT/CT-based dosimetry and 4-cc small-sphere VOI sampling of kidney activity concentration. Scans were performed at 1, 4, and 7 days after the 1st and the 4th administrations, and at 1 day only for other cycles. A mixed blood and whole-body planar scan-based approach was used for the bone marrow dosimetry assessment, but the limit of 2 Gy was not reached in any patient. The prescribed renal dose of 23 Gy was reached in 3 to 9 cycles in 62% of patients, and 49% of patients received more than 4 cycles. Most other patients stopped PRRT because of toxicity or disease progression. Tumour dose was not reported. Overall, the ORR and biochemical response rate were 24 and 67%, and the median PFS and OS were 27 and 43 mo., respectively. Most interestingly, there were statistically significant differences for all these four parameters between the subgroup of patients who have reached 23 Gy to the kidney vs. those who did not: 31% vs. 13% ORR, 80% vs. 45% biochemical response rate, 33 vs. 15 mo. median PFS, 54 vs. 25 mo. median OS. Of note, the 65 patients with midgut neuroendocrine tumour who reached 23 Gy to the kidney had median PFS and OS of 42 and 60 mo., respectively. This compares favourably with the outcomes of the patients in the 177Lu-DOTATATE arm of the NETTER-1 trial, at 28 and 42 mo., respectively [This group was the first to report results of a prospective clinical trial of personalised PRRT . In a siectively . While i177Lu-DOTATATE cycles until a renal BED of 27 Gy was reached . Of note, because there is a roughly consistent + 10% difference between absorbed dose and BED for 177Lu PRRT, this regime was quite similar to that of the Uppsala group described above, or at most slightly augmented [step 2). The dosimetry protocol was hybrid, with 5-timepoint whole-body planar (up to day 7) allowing to define the shape of the time-activity curve, which was then scaled using a single-timepoint quantitative SPECT/CT at 24 h. Patients received 1 to 9 cycles (median of 5 cycles) over a period of up to 97 weeks. The primary endpoint was the ORR 3 mo. after the last cycle of step 1 , and the results were as follows: PR in 16%, SD in 66%, and PD in 19% (n = 90). When the step 2 outcomes were also considered, the best ORR reached 2% CR, 32% PR, 61% SD and 4% PD. This illustrates that many patients are late responders to PRRT, although it is surprising that among 17 patients with initial PD, 13 were later found to have SD or better response. The median PFS and OS were 29 and 47 mo., respectively. Both were significantly longer as the delivered renal BED went from < 25 Gy, to 25–29 Gy, to > 29 Gy. The profile of clinical adverse events did not appear to differ from that of other PRRT studies. The laboratory toxicity data showed grade 3–4 rates of 9.4% for thrombocytopenia, 6.2% for neutropenia, 4.2% for leucopoenia, 1% for anaemia, and no grade 3–4 treatment-related renal toxicity.Final results of another Swedish clinical trial of dosimetry-based PRRT, the ILUMINET trial, were recently reported . In thisugmented . A subse177Lu-DOTATATE, with a personalised activity per cycle to deliver 23 Gy to the kidney. Like the Uppsala group, the renal dosimetry is based on 2-cm VOI sampling using quantitative SPECT/CT. Initially, we performed 3-timepoint imaging  at each cycle, and progressively reduced this to 2 timepoints (day 1 and 3) after the first cycle and one timepoint (day 3) after the subsequent cycles [We are conducting a single-arm trial of personalised PRRT in which patients with mixed neuroendocrine tumours receive four induction cycles of t cycles . We prest cycles . Initialt cycles . In 34 p90Y-DOTATOC PRRT [90Y-DOTATOC, with the first one being at a fixed activity of 4.4 GBq (or 1.85 GBq/m2 in two paediatric patients) and the activity of the two following cycles was prescribed to reach a maximum of 23 Gy to the kidney or 2 Gy to the bone marrow, with an absolute activity cap of 5.6 GBq. The post-treatment dosimetry protocol included 90Y-PET/CT over the kidney at 5 h, to quantify the activity, and 4-timepoint bremsstrahlung SPECT/CT at 6, 24, 48 and 72 h, to determine the bi-exponential kinetics. The bone marrow absorbed dose was derived from blood sampling. They found that in 85% of patients, the administered activity at cycles 2 and 3 differed by more than 20% from the empiric activity. This was due to the highly variable renal specific absorbed dose ranging from 0.32 to 3.0 Gy/GBq. No patients experienced grade 3–4 renal or hematologic toxicity. No efficacy results were reported.The group from Iowa performed a phase 2 trial of dosimetry-based TOC PRRT . 25 pati90Y-DOTATOC PRRT and 131I-MIBG RPT in a phase 1 trial [111In-octreotide (as a surrogate for 90Y-DOTATOC) and a diagnostic amount of 131I-MIBG, with double-isotope planar and SPECT/CT imaging and blood sampling at 1, 4, 24 and 48 h. They determined the dosimetry for the kidneys, target tumour lesions and the bone marrow (self-dose from blood counting and cross-dose from imaging), and prescribed the therapeutic activities of 90Y-DOTATOC and 131I-MIBG to deliver total cumulative absorbed doses targets of 19 Gy to the kidney and 1.5 Gy to the bone marrow, divided in 2 cycles. As compared with administering personalised 90Y-DOTATOC alone, they could slightly reduce the 90Y-DOTATOC activity prescription (from 5–10.8 to 2.8–8.7 GBq) to infuse 11.4–18.7 GBq 131I-MIBG the next day, with resulting per-lesion dose increases ranging from 34 to 362%. All subjects had stable disease at 6 mo. after cycle 2. One subject experienced temporary grade 3 thrombopenia and another one grade 2 renal toxicity. The authors initially planned for a 3 + 3 absorbed dose escalation study but interrupted it because of logistical challenges and their interest into switching to a combination of 177Lu-DOTATATE and high specific activity MIBG .The group from Iowa also reported on a series of three patients with midgut neuroendocrine tumour who were treated with combined  1 trial . These p131I of thyroid cancer, the oldest RPT that is still commonly practised worldwide, as well as for 177Lu-PSMA-RLT of prostate cancer, the new blockbuster RPT, prospective data for dosimetry-driven regimes is not yet available.Above, we reviewed published results of prospective studies in which imaging-based dosimetry has been used to personalise RPT. It is noteworthy that for 131I has been administered for about 80 years to patients with differentiated thyroid cancer. The most common practice is to administer lower fixed activities in the context of thyroid remnant ablation (e.g. 1.1 to 3.7 GBq), or higher fixed activity to treat patients with documented metastatic disease or at higher risk thereof after surgery (e.g. 5.6 to 7.4 GBq). An imaging dosimetry-based approach has been often cited, i.e. that of Benua and Leeper, in which absorbed dose limits to the bone marrow (2 Gy) and to the lung (30 Gy) are imposed. These limits have been deemed equivalent to a whole-body activity retention on the 48 h whole-body planar scan of 4.4 or 3.0 GBq, in the absence or presence of diffuse lung metastases, respectively [124I-PET/CT for pre-treatment dosimetry to adjust the 131I activity to deliver 80 Gy to the soft tissue lesions and 650 Gy to the bone lesions, without exceeding 2 Gy to the bone marrow as estimated by blood sampling (NCT05299437).ectively , 35. Pro177Lu-PSMA-617 as compared to best supportive care, PSMA-RLT is poised to soon become the most prominent RPT in terms of patient numbers [177Lu-PSMA-617 vs. cabazitaxel chemotherapy [177Lu-PSMA-617 has been established to six 6-weekly cycles of 7.4 GBq. No prospective results and no entry on ClinicalTrials.gov were found regarding dosimetry-based PSMA-RLT. Nevertheless, the rationale for dosimetry-driven PSMA-RLT is the same as for other RPTs: there is a high interpatient variability in specific absorbed dose to critical organs  and the current fixed-activity regimes are well tolerated, implying that a majority of patients are undertreated from a dosimetry perspective [177Lu-PSMA-617, those who biochemically responded (i.e. prostate-specific antigen decline > 50%) received a median mean tumour absorbed dose of 14.1 Gy, as compared with 9.6 Gy for those who did not [PSMA-RLT has rapidly emerged over the last decade. With the positive results of the VISION trial showing prolonged PFS and OS following  numbers . The Ausotherapy . As per spective , 3, 36. The cumulative evidence drawn from the studies presented here, covering a variety of therapeutic beta-emitting radiopharmaceuticals used in a range of different oncological situations, as well as varied dosimetry approaches (including both pre-treatment and per-treatment dosimetry) broadly illustrates that personalised RPT based on dosimetry (1) is feasible, (2) is safe, and (3) offers the prospect of improved clinical outcomes vs. fixed-activity empiric regimes.A critical aspect for wide adoption of any dosimetry-based RPT regime is its feasibility in routine clinical practice. While the required SPECT/CT and/or PET/CT equipment is readily available in most centres offering RPT, a significant logistical hurdle that may arise for many centres is the limited technologist workforce to perform multi-timepoint scanning for a large number of treated patients on top of the usual diagnostic imaging workload. Solutions include the rationalisation of the number of imaging timepoints. Recently, there has been a growing interest in one-timepoint scanning protocols, in which a carefully chosen scanning timepoint  would allow to derive a dosimetry estimate with a reasonably small uncertainty , 38. How86Y, 89Zr, 64Cu, 124I for PET, or 123I, 111In for SPECT) or a low activity of the therapeutic compound, versus performing only post-treatment dosimetry to personalise all but the first cycle based on dosimetry measurements. The former approach is obviously essential in the case of a single-cycle regime. While there is a risk that the low-dose tumour irradiation during the pre-treatment dosimetry induces radioresistance (a.k.a. stunning), the main advantage is to deliver a first (or single) cycle during which tumour irradiation will be maximised, potentially leading to enhanced cytotoxicity among radiation-naïve tumour cells (i.e. before these acquire significant radioresistance). In the case of a multi-cycle regime, however, performing a full pre-treatment dosimetry performed over multiple days adds to the logistical and patient burdens and can significantly delay the initiation of the treatment. Further data will be required to find out if the therapeutic benefits would outweigh the disadvantages of the extra diagnostic procedure in this setting.Another facet of feasibility is the question of performing full pre-treatment dosimetry using either a surrogate long-lived diagnostic tracer  and the unfavourable emission spectrum for many of these, personalised RPT is still achievable. Long-lived PET or SPECT surrogate diagnostic tracers can be used for pre-treatment dosimetry, or co-injected with the alpha-emitting radiopharmaceutical for per-treatment dosimetry. Co-injection of alpha and beta radiotherapeutics having the same pharmaceutical moiety is another approach to consider: the beta emitter could synergise with the alpha emitter by improving crossfire capability for better coverage of heterogeneous lesions, while also enabling high-quality imaging for real-time dosimetry and response assessment.177Lu-based PRRT and PSMA-RLT when administered at fixed activity [131I-MIBG trial presented above, the treatment was not truly personalised for most patients who received the maximum (or close to) 18.5 GBq/cycle, and this has led to 26% of patients not being able to receive the second cycle because of hematologic toxicity, possibly depriving them of more sustained clinical benefits [177Lu and high-activity MIBG RPTs also supports the hypothesis of a certain proportionality, at the population level, between the risks of deterministic hematologic effects (subacute myelosuppression) vs. the stochastic effects (e.g. MDS/AML): approximately 10% vs. 1%, respectively, for 177Lu, and 70% vs. 7%, respectively, for high-activity MIBG. Furthermore, the non-myeloablative radioimmunotherapy data falls somewhere in between. Accordingly, the subacute hematologic toxicity rate of a given RPT regime is likely predictive of the incidence of longer-term complication rate. Fractionation can be an important aspect to consider when establishing an RTP regime, and it is possible that more frequent, lower-activity MIBG cycles may be easier to tolerate, while allowing for equal or even greater efficacy if interruption for toxicity can be avoided. For RPT, as for any anticancer treatment, seeking an appropriate balance between risks and potential benefits remains of paramount importance.RPT is, in general, reputed for its excellent safety profile as compared to other oncological treatments such as chemotherapy. This is particularly true for activity , 27. Thebenefits .. The ag90Y radioembolisation based on tumour absorbed dose prescription over that for the standard regime has been demonstrated with a high level of evidence, i.e. in a multicentre randomised controlled trial [177Lu PRRT [177Lu PRRT or PSMA-RLT), it can be foreseen that future development of new systemic RPTs will be dosimetry-based from the start. But until then, the reference standard of practice will remain that of fixed activity, which has prevailed since the introduction of 131I for thyroid cancer until today, with the recent approval of empiric 177Lu-PSMA-617 RLT for prostate cancer [The superior efficacy of ed trial . Such de7Lu PRRT –14.. Thee cancer .177Lu-DOTATATE consisting in four 3-monthly induction cycles of up to 5.55 GBq, followed by eight 6-monthly maintenance cycles of up to 3.7 GBq. While the median PFS in their cohort of mixed neuroendocrine tumours was 36.1 mo., that in the subgroup of patients with midgut tumours was impressive at 47.7 mo [Another aspect worth considering in the design of a personalised RPT regime is the biological behaviour of the targeted tumour. For example, more indolent cancers such as well-differentiated neuroendocrine tumours may benefit from prolonged exposure to PRRT. Indeed, in the two Swedish studies presented above, the PFS and OS tended to be longer for patients who received the prescribed renal dose vs. those who did not. Because of the fixed activity per cycle of 7.4 GBq, most patients underwent more than 4 cycles, meaning that their PRRT extended beyond 6 mo. . Further substantiating this hypothesis are the results from a Canadian phase 2 trial of low-activity  47.7 mo . FurtherThe current decade will undoubtedly see a tremendous growth in the field of RPT. There has never been a better opportunity to modernise the practice of RPT and make it on par with that of external radiotherapy: personalised and dosimetry-guided. RPT has a unique advantage above ordinary drugs, as it enables non-invasive assessment of the biokinetics of its active ingredient – i.e., dosimetry – at the patient level. While there is still much to learn on how to best deliver RPT, the cumulative evidence to date fully supports the acceleration of clinical research initiatives in dosimetry-based RPT. An eloquent demonstration has been made that personalised radioembolisation is a better treatment than the conservative standard approach, and this now needs to be evidenced for systemic RPTs. Finally, dosimetry-guided RPT represents a more equitable approach for the diversity of patients we treat, because it allows each of them to receive an equivalent treatment from a radiation delivery perspective which is a clear theoretical benefit over fixed activity RPT.


In patients, image ratings were similar for all parameters except for “conspicuity of FLLs” which was rated significantly lower on L1-DWI vs. conv-DWI  in group A. In five patients, 11/349 FLLs were not detectable on L1-DWI, but on conv-DWI. L1-regularized iterative reconstruction of single-shot EPI DWI can accelerate image acquisition or improve spatial resolution. However, our finding that FLLs were non-detectable on L1-DWI warrants further research.To investigate whether combining L1-regularized iterative sensitivity encoding (SENSE) reconstruction and single-shot echo planar imaging (EPI) is useful in hepatic DWI. Single-shot EPI-DWI with L1-regularized iterative SENSE reconstruction (L1-DWI) and conventional parallel imaging-based reconstruction (conv-DWI) in liver MRI were compared in volunteers and patients. For the patient cohort, 75 subjects (60 ± 13 years) with 349 focal liver lesions (FLL) were included. Patient groups A and B were used to reduce acquisition time or improve spatial resolution, respectively. Image parameters were rated on a 5-point scale. The number of FLLs was recorded; in case of discrepancy, the reason for non-detectability was analyzed. In volunteers, higher signal-to-noise ratio (24.4 ± 5.6 vs. 12.2 ± 2.3,  First reported by Lustig et al. in 2007, CS uses the sparsity of image data and attempts to avoid undersampling artifacts by using incoherent undersampling with iterative reconstruction7. CS has been shown to yield comparable image quality compared to conventional imaging10. Most research projects focused on the use of CS to accelerate acquisition in dynamic contrast enhanced imaging of the liver and the breast, where fast image acquisition is of key importance13.Numerous MRI techniques have been developed to accelerate acquisition time of MR imaging by skipping data in κ-space such as keyhole techniques, parallel imaging, and, more recently, compressed sensing (CS)6. Similarly, the faster acquisition can be invested to increase spatial resolution at a given acquisition time.Diffusion weighted imaging (DWI) is a pulse sequence that could benefit from the principle of CS; not only for accelerated acquisition as the case with conventional parallel imaging, but also for improved signal-to-noise ratio (SNR) via denoising during iterative reconstruction16. There is even evidence to suggest that DWI is more important for the detection of FLLs than standard structural liver MRI18. Recently wavelet-based denoising as used in the CS framework has been combined with parallel imaging that derives a L1-regularized iterative SENSE reconstruction showing effective in single-shot echo-planar imaging (EPI) based DWI noise reduction20.DWI plays an important role in the detection and characterization of focal liver lesions (FLLs)Therefore, the aim of our study was to investigate CS-based reconstruction using L1-regularized iterative SENSE in EPI DWI (L1-DWI) in healthy volunteers and a cohort of patients undergoing liver MRI in direct comparison to conventional parallel imaging based reconstruction (conv-DWI), for both purposes, i.e. increased acquisition speed and increased spatial resolution.This comparative analysis was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee at the RWTH Aachen Faculty of Medicine (EK 226/20). Written informed consent was waived.For quantitative assessment of the signal-to-noise ratio (SNR) and apparent diffusion coefficient (ADC), L1-DWI was performed in healthy volunteers and compared to conv-DWI. Details are described below in MR Imaging and Image Analysis.For investigation of its potential clinical utility, L1-DWI was applied in therapy-naïve patients, who received standard multi-parametric liver MRI for clinical indications from November 2019 through February 2020 for either search of liver metastases of a newly diagnosed malignancy or diagnosis or staging of primary liver tumors. All patients underwent a standardized multiparametric liver MRI protocol, and conv-DWI plus L1-DWI that were to be acquired in randomized order.To investigate the potential utility of L1-DWI in terms of reduced acquisition time or improved spatial resolution, two different types of L1-DWI protocols were used:During the first half of the study period (November through December 2019), patients underwent conv-DWI plus L1-DWI, where CS-based reconstruction was used to reduce acquisition time of conv-DWI (group A); during the second half of the study period (January through February 2020), CS-based reconstruction was invested to improve spatial resolution compared with conv-DWI (group B). Accordingly, in group A, L1-DWI was acquired with the same spatial resolution as conv-DWI, but faster; in group B, L1-DWI were acquired with similar acquisition time as conv-DWI but had a higher spatial resolution. In both patient groups, the same acceleration factor of 3 was applied as in healthy volunteer exams.If a patient underwent more than one liver MRI study during the study period, only the first examination was included to avoid repetitive observations of the same patient to confound the results.All MR examinations were performed at a 1.5 Tesla system . A torso phased array coil was used in all studies. The standard liver MRI protocol consisted of the following pulse sequences: axial breath-hold dual-echo T1 gradient echo in and opposed phase, axial T2-weighted turbo-spin echo (T2w TSE) sequence with and without spectral-selective fat suppression, coronal T2w TSE-sequence, a dynamic contrast enhanced series consisting of axial T1-weighted turbo field echo (Turbo i.e. gradient echo) sequence before and after contrast media injection (Gadobutrol or Gd-EOB-DTPB Dinatrium), followed by late phase enhanced-T1-weighted High Resolution Isotropic Volume Examination (eTHRIVE) using a fat-suppressed gradient-echo pulse sequence.9. This provided relatively shorter EPI train length, echo time, and repetition time, compared to those in conv-DWI (acceleration factor 2), and resulted in a slightly reduced nominal scan time. For conv-DWI reconstruction, conventional SENSE was applied to the undersampled data. In addition to that, scan parameters of both sequences were matched as closely as possible, with shortest possible repetition times and same number of slices in the interleaved order in each case. For L1-DWI reconstruction, a regularized, iterative L1-norm minimization was applied assuring image sparsity in the wavelet domain and data consistency, as in typical CS reconstruction by taking the SENSE coil information into account28. Standard denoising was applied , anonymized for patient data  and blinded for acquisition parameters .24. In short, identical pulse sequence was performed without radio frequency excitation for the same imaging volume and separate noise-only images in each subject were obtained to account for influence from parallel imaging or CS reconstruction. As it prolonged the examination times, i.e., doubled corresponding L1-DWI or conv-DWI scan times, this evaluation was performed only in the volunteer studies. Regions of interest (ROIs) were carefully placed in the liver parenchyma of L1-DWI and conv-DWI with uniform signal without vessels or artifacts as well as in the corresponding noise map. Two ROIs were placed per volunteer. The mean values and standard deviations from each ROI were extracted to compute SNR and averaged for comparison. The same criteria of ROI selection also applied to quantification of the apparent diffusion coefficient (ADC).For signal-to-noise ratio (SNR) evaluation, additional noise maps were acquired for both L1-DWI and conv-DWI in volunteer measurements. The method was previously describedFor qualitative image analysis, two radiologists with 10 years (AB) and 4 years (MB) of experience in interpretation of abdominal MRI reviewed the CS- and conv-DWI data sets side-by-side, yet independently and blinded to the clinical information as described above. Image quality was visually scored according to a 5-point scale regarding the following features: (1) sharpness of the liver contours, (2) delineation of intrahepatic vessels, (3) signal homogeneity of the liver parenchyma and (4) conspicuity of FLLs, from 1 = poor to 5 = excellent; (5) image noise and (6) motion artefacts were evaluated using a 5-point scale ranging from 1 = severe to 5 = none.During a separate reading session done more than 16 weeks after the first session on image quality assessment, the two readers, again blinded to the type of DWI acquisition, reviewed the images in randomized order to compare the detection of FLLs. The number of FLLs for each DWI study of each patient was recorded.When a FLL was missed on one of the pulse sequences (L1-DWI or conv-DWI), we investigated the respective cause: Whether the FLL was missed because of a reading failure, or whether, also in retrospect, i.e. with knowledge about the location of the FLL, the FLL was not visible; in this latter case, we recorded possible reasons for non-detectability such as local image degradation due to motion or pulsation artefacts.In case of a discrepancy of the number of visible FLLs between L1-DWI and conv-DWI, we used all pulse sequences of the multiparametric hepatic MRI protocol, plus follow-up information of further MRI studies to clarify whether or not the DWI finding corresponded to a true FLL or to an artefact.We also assessed the respective size and clinical relevance of the missed FLLs in terms of their implications on further patient management.t-test. For each image quality parameter, the mean and SD were calculated based on the ratings of the two readers and the resulting scores for L1-DWI and conv-DWI were compared by using a Wilcoxon rank sum test. The level of statistical significance was set at α = 0.05. The interrater variability was assessed by using weighted Cohens Kappa for each rated criterion at a 95% confidence interval. A coefficient value < 0.00 indicated poor agreement, 0.00–0.20 slight agreement, 0.21–0.4 fair agreement, 0.41–0.6 moderate agreement, 0.61–0.8 substantial agreement and 0.81–1.00 almost perfect agreement25. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 25.0.Data were reported as mean and SD. Differences in continuous variables were evaluated with a paired Twelve healthy subjects  with different body sizes (1.57 to 1.93 m) and no known illness were included in the volunteer group. Figure Accordingly, the final patient cohort consisted of 75 patients. Patient demographics and details on their primary tumors are given in Table Of the 75 patients, 57 patients had at least one and up to 30 FLLs. In group A, 101 FLLs were observed in 20/28 patients. In group B, 248 FLLs were observed in 37/47 patients.2  and 800 s/mm2 . Liver ADC values were deemed significantly different between L1-DWI and conv-DWI , whereas SD of ADC value in L1-DWI was found significantly lower than that in conv-DWI .In general, reduced background noise and better structural delineation could be visualized in L1-DWI compared to conv-DWI, as shown in Fig. p = 0.006).Results are given in Table In group B, image quality ratings did not differ significantly; although also here, a tendency for somewhat higher FLL conspicuity in conv-DWI was observed, this feature did not reach statistical significance. For representative images of group A and group B see Fig. The two readers showed slight to substantial agreement for the rated image quality parameters  were not detected on L1-DWI, but on the patient’s conv-DWI. Even in retrospect, these two FLLs were not visible on L1-DWI. An analysis of why these two FLLs were occult on L1-DWI showed that one FLL happened to be obscured by pulsation artefacts at the site of the FLL on L1-DWI. For the other missed FLL, no apparent reason could be identified , 9/248 FLLs (4%), between 3 and 7 mm in diameter, were not prospectively detected on L1-DWI, but prospectively called on the respective patient’s conv-DWI. Even in retrospect, these lesions were not visible on L1-DWI  to note that non-detectability of lesions in L1-DWI was not explainable by or attributable to e.g. artefact degradation, but was observed also in L1-DWI images that appeared to offer perfect image quality.CS has been introduced to accelerate data sampling in MRI. Most studies on the clinical application of CS focused on its use to shorten acquisition time, and analyzed the resulting image quality. Most authors found that CS allows a reduction of image acquisition without loss of image quality—which is in good agreement with our findings. However, much less information is available on the diagnostic accuracy of such heavily accelerated pulse sequences. One study, by Nam et al. investigated the use of CS for dynamic contrast enhanced liver MRI including detection of FLLs in a multi-reader study and found a similar diagnostic accuracy of CS Dixon-gradient recall echo over standard non-CS Dixon-gradient recall echo. However, in that study, no head-to-head comparison of individual detected lesions was performed.26. Higher ADC values in L1-DWI compared to conv-DWI has also been reported previously in different anatomies including brain and prostate26. A possible cause may be a shorter repetition time ) used in L1-DWI27 or higher noise in conventional SENSE images using parallel imaging. However, in the current study a quantitative SNR improvement in volunteer scans was not reflected by qualitative scores in patient exams, where no improvement was shown for L1-DWI in image noise and artifacts rating. While there may be various factors contributing to this discrepancy, including local ROI selection vs. global visual inspection, body size and composition variabilities in the volunteer vs. patient cohorts, etc., detailed investigations are needed to study its impact in image quality and, particularly, delineation of normal appearing tissues and lesions28.The observed SNR improvement in L1-DWI in volunteer scans most likely benefits from the iterative denoising process in the wavelet domain, in which the noise patterns are sparsely represented, as well as a shorted echo time due to higher acceleration factor used in L1-DWI. Lower standard deviations in ADC of L1-DWI have shown less variability and may indicate a higher precision and reproducibility in ADC assessment, which is in accordance to other studiesThe positive impact of CS on image quality could be expected to improve detectability of FLLs, e.g. by reducing motion artefacts in protocols that exploit fast data acquisition with CS, or by shortening the echo train length and thus improving SNR in DWI with CS. On the other hand, with the undersampling that is employed for CS, it is conceivable that small lesions are “levelled out” and thus not displayed with the true signal intensity that they should have on DWI or structural MRI. Accordingly, there is a need for research that compares the detectability of such small lesions in heavily accelerated pulse sequences.In our study, 2 and 4% of FLLs observed in 4 and 6% of patients of group A and B, respectively, were detected by conv-DWI, but were not visible on L1-DWI. The majority of patients in our cohort, including the five patients who had FLLs missed on L1-DWI, had multiple FLLs. Therefore, the missed FLLs would not have led to a change of patient management. However, it is possible that in future patients, e.g. with colorectal cancer in preparation of major liver surgery, detectability of even small additional metastases may do impact the treatment plan.A further analysis of the type of FLLs missed on L1-DWI revealed that all missed FLLs were small, 7 mm or less in diameter, i.e. had a size similar to that of the section thickness of our DWI protocol. Small FLLs can always be missed on DWI in case there happens to be image degradation due to artefacts at the site of a lesion, or in case partial volume averaging leads to reduced contrast. In these latter situations, however, there should at least be a subtle signal intensity difference on a post-hoc analysis of the respective images—which was not the cases where FLLs were missed in L1-DWI in our study cohort. Also, a post-hoc analysis of image quality at the site of the missed FLLs revealed no artefact degradation as a possible explanation for such a misdetection.28, the same equidistant k-space acquisition pattern as in conventional single-shot EPI was used here for CS-based reconstruction, instead of a specifically tailored incoherent sampling pattern7. This might also limit the denoising performance. On the other hand, different imaging parameters between L1-DWI and conv-DWI such as echo times, and therefore scan time, may also contribute to lesion conspicuity, for example, due to induced image contrast change. Consequently, a systematic evaluation of the scan set ups in clinical settings is needed. The setting of the parameters should not only be chosen based on the image quality, but also based on the visualization of small FLLs.One explanation of missed FLLs in L1-DWI in group B is because of their small size and reduced SNR in the image associated with higher spatial resolution. Moreover, the contrast to noise may be further decreased due to CS denoising that already occurred in every DWI measurement in the resource images. In this case, although the background tissue, i.e. liver parenchyma, appears smoother and less noisy via CS denoising, the visibility of small FLLs may become less apparent, which can no longer be retrieved by the sparsifying constraint in the CS-based reconstruction with L1-regularized SENSE including wavelet-based denoising, even after adding multiple measurements or acquisitions (see Figure, Supplemental Digital Content 29, in which case the minimum repetition time should be determined by T1 of the background tissue to reach thermal equilibrium30.Our study has several limitations. First, the study cohort was relatively small. In addition, the subgroups differed in the number of patients, which is due to the fact that the enrollment of patients was fixed at two months for each group in our study design. Second, the study cohort consisted of a heterogeneous patient population. On the other hand, this may also be considered advantageous because we assessed the feasibility of L1-DWI in various clinical settings. Third, most FLLs were not confirmed by pathology. Accordingly, although we did our best to provide a sound composite ground truth, it is conceivable that detected and non-detected small FLL did not correspond to a relevant pathologic condition. Finally, our study design did not include having fewer number of signal averages as another way to reduce the scan timeIn conclusion, although L1-DWI can be used to reduce acquisition time or increase spatial resolution, and although measured SNR and stability of ADC values are improved, its image quality in clinical patients appears to be mostly comparable, while detection of FLLs is affected. Further investigations on optimal scan setups are needed before implementation of L1-DWI in clinical practice and should be done not only based on image quality but also visualization of small FLLs.Supplementary Information.


COVID-19 has led to restrictions on movements and lockdown measures, which have resulted to higher utilization of over-the-counter drugs compared to prescription-only drugs. This study determined the prevalence, pattern and predictors of self-medication for COVID-19 prevention and treatment.A cross-sectional survey was conducted between October and November 2021 among the residents of Umuahia, Abia State. The respondents were selected using a snowball sampling technique, and a self-administered semi-structured questionnaire was used to collect data on the variables via Google forms. Descriptive, bivariate and multivariate analyses were done using IBM SPSS version 26. The level of significance was set at 5%.A total of 469 respondents participated in the survey. The overall prevalence of self-medication for COVID-19 prevention and treatment was 30.3% (95%CI: 26.7–34.1). The most commonly used medication was herbal products (43.7%). This was mainly self-prepared (41.5%). The major source of information for self-medication was from family members (39.4%). The majority of the respondents reported fear of isolation (76.3%), followed by fear of stigmatization (75.7%) as the triggers of self-medication. Older age , lower educational status [No formal education ], [Primary education ] and perception to cost  were the predictors of self-medication.Every one in three residents of Umuahia, Abia State, practiced self-medication for COVID-19 prevention and treatment. Some economic and socio-demographic factors were significantly associated with self-medication. We recommend intensifying public awareness campaigns on the risk of self-medication.The online version contains supplementary material available at 10.1186/s40545-022-00429-9. The World Health Organization (WHO) declared COVID-19, a newly emerging disease of public health emergency of international concern on 30th January 2020 [According to WHO, self-medication has been defined as the selection and use of medicine by individuals to treat self-recognized symptoms or illnesses . This noSelf-medication is known to exhibit both positive and negative outcomes . The terA study in Kenya noted an increase in self-medication from 36.2% pre-pandemic to 60.2% amid the pandemic . Self-meVarious motivations for self-medication have been reported, including previous disease experience, perceived cues to action, high cost of medical services, existing bureaucracy in health facilities, and weak regulatory activities , 27. SelThis was a descriptive cross-sectional study conducted in Umuahia, Abia State. Umuahia is the capital of Abia state, one of the five states in the South-East zone of Nigeria. It has an estimated population of 303,787 in 2018 projected from the 2006 national population census with an annual growth rate of 2.7% . It has Adult residents in Umuahia made up the study population. The inclusion criteria included those aged ≥ 18 years and living in Umuahia for the past 3 months prior to the study period. Eligible participants who had chronic or debilitating illnesses interfering with communication were excluded from the study. A chronic or debilitating illness “is a physical or mental health condition that lasts more than one year and causes functional restrictions or requires ongoing monitoring or treatment” .n = (ZA)2pq/d2. The minimum sample size was estimated to be 414. A non-response rate of 10% was assumed.Using the proportion of 41% of self-medication for COVID-19 prevention and treatment in a previous study conducted in Nigeria and prec. This was done through the contact lists of the researchers, in addition to neighbours, friends and relatives on different fora. They were encouraged to further share the link with their relatives, friends, colleagues and other broader social network. On a daily basis, a crafted reminder message containing the link to the questionnaire was sent out to the targeted WhatsApp, Facebook messenger and Telegram groups.An extensive literature review was performed and the structure of the questionnaire was developed based on published research. Using Google Forms, which is a cloud-based survey tool powered by Google, a structured questionnaire was created for data collection over a month (October 2021). The questionnaire was validated using the face and content validity techniques. The introductory section emphasized the privacy of the respondents’ responses. The pretest was done in a community outside the study area. This helped to improve the diction of the questionnaire. The questionnaire has different sections. Section 1 includes information on sociodemographics such as age, sex, marital status, religion, denomination, occupation status and income. Section 2 addresses knowledge of self-medication. Section 3 focuses on the prevalence of self-medication. Section 4 contains information on self-medication practices and Sect. 5 addresses the triggers of self-medication. The questionnaire link was distributed to various social media platforms, including Telegram, Facebook Messenger and WhatsApp MessengerThe dependent variable was self-medication for COVID-19 prevention and treatment. It was coded as binary responses, ‘yes’ as ‘1’ and ‘no’ as ‘0’. The independent variables included the sociodemographics, self-medication practices and triggers of self-medication.Data coding, entry, cleaning, and analysis were done using IBM SPSS version 26 statistical program for Windows. Descriptive statistics was used to characterize the sample and study variables. Associations between independent variables and self-medication for COVID-19 prevention and treatment were assessed with cross-tabulations, followed by multivariate analysis using logistic regression to determine the significant independent predictors of self-medication for COVID-19 prevention and treatment. The level of significance was predetermined at a p-value of less than 0.05.A total of 469 respondents participated in the survey. The mean age was 39.9 ± 13.5 years. The less than 30 years age group 129 (27.5%) and 31–40 years age group 128 (27.3%) were similar in proportion. Females 267 (56.9%) were more prevalent compared to males. Among the respondents, 203 (43.3%) had attained tertiary education and 288 (61.4%) were married. The majority of the respondents were Christians 460 (98.1%) and 219 (46.7%) of them belonged to the orthodox denomination. A greater proportion of the respondents were salary earners 199 (42.4%) with an equal proportion of the respondents 140 (29.9%) each belonging to the income categories of < 50,000 ($121) and > 100,000 ($242)  were aware of self-medication. More than three-quarters of the respondents 405 (88.4%) gave the correct definition of self-medication and majority of them 394 (86.0%) believed that self-medication was harmful. The prevalence of self-medication for the prevention and treatment of COVID-19 was 30.3% (95% CI: 26.7–34.1).Figure Figure As shown in Fig. Figure In the bivariate logistic regression model, age, educational status, marital status and perception of the cost of self-medication were significantly associated with the practice of self-medication in the prevention and treatment of COVID-19. Those aged over 40 were 80% more likely to practice self-medication compared to those younger than 40 years . Those with no formal or primary education were more likely to self-medicate compared to the postgraduate degree holders . Similarly, those who had attained secondary education were also more likely to self-medicate compared to the postgraduates . Respondents who were widowed or separated were threefold more likely to self-medicate compared to singles . Those who perceived that self-medication was cheaper were more likely to self-medicate compared to their counterparts  , no formal education , primary education  and the perception of self-medication as cheap   , Togo  were more likely to self-medicate compared to the younger age groups (< 40 years). This finding agreed with other studies conducted in Nigeria, Serbia, Peru and China where higher odds of self-medication were observed among older persons , 45–47. Self-medication was significantly associated with level of education as those without tertiary education were more likely to self-medicate compared to those who had attained tertiary education. This is similar to the findings of studies in Nigeria, Iran and Middle East –56. HoweSelf-medication was associated with perceived cost of medication. Those who believed that self-medication was cheaper had higher odds of self-medication compared to their counterparts. As evidenced in studies , 59, cosThe major strength of this study is that it is among the first studies in southeastern Nigeria to explore self-medication for COVID-19 prevention to the best of our searches. Another strength is that the general population was involved, in contrast to other studies involving only specified populations  or institutionalized groups . Few limitations were observed in this study. There was a possibility of selection bias as only those who had access to smart devices connected to the internet could participate in the study. This could affect the generalizability of the findings to the general populace. Use of self-reported data, as in this study, is prone to recall bias and social desirability bias. These were mitigated by attaching a showcard of possible drugs for easy identification and assuring the respondents of full confidentiality of their responses.Self-medication was prevalent among one-third of residents in Umuahia, Abia State. The most commonly used medication was herbal products mostly self-prepared. The major source of information for self-medication in this current study were family members and friends. Age, educational status and perception of cost significantly influenced self-medication practices for the prevention and treatment of COVID-19. We therefore, recommend that stakeholders conduct awareness and sensitization campaigns on the risks of self-medication targeting the older age groups and those with low educational status. Additionally, there is a need to create public enlightenment programmes on the hazards of herbal medicine use to avert the potential adverse effects (Additional files Additional file 1: STROBE guideline checklist.Additional file 2: Questionnaire.


To estimate the risk of recurrent cardiovascular events in a real-world population of very high-risk Korean patients with prior myocardial infarction (MI), ischemic stroke (IS), or symptomatic peripheral artery disease (sPAD), similar to the Further cardiovascular OUtcomes Research with proprotein convertase subtilisin–kexin type 9 Inhibition in subjects with Elevated Risk (FOURIER) trial population.This retrospective study used the Asan Medical Center Heart Registry database built on electronic medical records (EMR) from 2000 to 2016. Patients with a history of clinically evident atherosclerotic cardiovascular disease (ASCVD) with multiple risk factors were followed up for 3 years. The primary endpoint was a composite of MI, stroke, hospitalization for unstable angina, coronary revascularization, and all-cause mortality.Among 15,820 patients, the 3-year cumulative incidence of the composite primary endpoint was 15.3% and the 3-year incidence rate was 5.7 (95% CI 5.5–5.9) per 100 person-years. At individual endpoints, the rates of deaths, MI, and IS were 0.4 (0.3–0.4), 0.9 (0.8–0.9), and 0.8 (0.7–0.9), respectively. The risk of the primary endpoint did not differ significantly between recipients of different intensities of statin therapy. Low-density lipoprotein cholesterol (LDL-C) goals were only achieved in 24.4% of patients during the first year of follow-up.By analyzing EMR data representing routine practice in Korea, we found that patients with very high-risk ASCVD were at substantial risk of further cardiovascular events in 3 years. Given the observed risk of recurrent events with suboptimal lipid management by statin, additional treatment to control LDL-C might be necessary to reduce the burden of further cardiovascular events for very high-risk ASCVD patients.The online version contains supplementary material available at 10.1007/s10557-021-07255-2. Cardiovascular disease (CVD) is the leading cause of death globally . PatientThe Further cardiovascular OUtcomes Research with proprotein convertase subtilisin–kexin type 9 (PCSK9) Inhibition in subjects with Elevated Risk (FOURIER) trial demonstrated the risk of secondary CVD events among high-risk patients and showed that adding evolocumab to statin therapy reduced the risk of recurrent cardiovascular events in patients with clinically evident atherosclerotic cardiovascular disease (ASCVD) . The majThus, the purpose of the current study, using electronic medical records (EMR) data from a tertiary hospital, was to obtain information about the clinical characteristics and to estimate the rates of cardiovascular outcomes in very high-risk Korean patients with prior myocardial infarction (MI), ischemic stroke (IS), or symptomatic peripheral artery disease (sPAD) who met the inclusion criteria for the FOURIER trial. In addition, we tried to evaluate the real-world treatment pattern of LDL-C for the very high-risk Korean population.A retrospective observational cohort study was conducted using EMR data from a large tertiary hospital in Korea. The study included adult patients at high risk of cardiovascular events and receiving statin therapy, who were followed for the occurrence of subsequent cardiovascular events. The study period was from 1 January 2000 to 30 November 2016.Data were obtained from the Asan biomedical research environment database, which is a data warehouse system  for the The study included patients from the AMC-HR who had a history of clinically evident cardiovascular disease  and at least 1 major risk factor or at least 2 minor risk factors , coronary revascularization (coronary artery bypass grafting [CABG] or percutaneous coronary intervention [PCI]), and all-cause mortality at 3-year follow-up. This mirrored the primary endpoint in the FOURIER trial except that cardiovascular-related death was replaced with all-cause mortality for the current study. The secondary endpoint was a composite of MI, stroke, and all-cause mortality.The follow-up period continued through to 30 November 2016, to ensure that all patients had the opportunity for a 3-year follow-up evaluation. Mortality was captured through documentation of mortality in EMR based upon national health insurance information. Cardiovascular events, including MI, UA, and stroke, were captured by identifying hospitalizations with a relevant primary or secondary ICD-10 diagnosis and adjudicating the event in conjunction with related laboratory results and reports on imaging studies by cardiologists and neurologists. Repeat revascularization was identified by the presence of cost codes for CABG or PCI, with final confirmation by a cardiologist based on the notes for the procedure. Definitions and associated ICD-10 or claim codes for the individual outcome variables are provided in Online Resource t test or the Wilcoxon rank-sum test, and categorical variables were compared using χ2 statistics or Fisher’s exact test, as appropriate.Continuous variables were presented as mean values with standard deviation and categorical variables as numbers with percentages. Continuous variables were compared using the Student Incidence rates for the outcomes of interest were calculated as the number of first events divided by the total follow-up person-time at risk until the event or the end of 3-year follow-up, expressed as rates per 100 person-years. Cumulative incidence and survival curves were generated using the Kaplan–Meier method.2), hypertension, diabetes, current smoking, and medications . Cox-proportional hazard regression models were also used to identify risk factors contributing to the primary and secondary outcomes and to all-cause mortality.Multivariable Cox-proportional hazard regression models were applied to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the primary and secondary outcomes and for all-cause mortality, according to statin dose. The models included adjustment for age, gender, renal function .A two-tailed Among subjects enrolled in the AMC-HR between 1 January 2000 and 30 November 2013, a total of 32,850 had a history of clinically evident ASCVD and at least 1 major risk factor or at least 2 minor risk factors. After screening, 17,030 of these patients were excluded because they were aged < 40 or > 85 years, had a recent MI or stroke, did not have blood LDL-C levels available, were not receiving a statin, had uncontrolled hypertension, or had a history of hemorrhagic stroke. This resulted in a final study cohort of 15,820 patients, comprising 5419 with a history of MI, 8950 with a history of IS, and 1451 with sPAD , and receiving non-statin lipid-lowering treatment, aspirin or P2Y12 inhibitors, beta-blockers, or RAAS inhibitors. Factors associated with an increased risk of meeting the secondary endpoint included age ≥ 65 years, diabetes, eGFR < 60 mL/min/1.73 m2, and treatment with beta-blockers or RAAS inhibitors. Factors significantly associated with an increased risk of all-cause mortality included age ≥ 65 years, diabetes, eGFR < 60 mL/min/1.73 m2, and treatment with beta-blockers.Results of the analysis of potential risk factors contributing to cardiovascular outcomes within 3 years in the AMC-HR cohort are summarized in Table LDL-C levels were re-evaluated within 1 year of the index event in 60.8% of the AMC-HR cohort, with no marked difference seen between subgroups based on the intensity of statin treatment that was being received at the time of the index event . No significant relationship was found between statin intensity and the risk of meeting the study’s primary or secondary endpoints, where the majority used a moderate-intensity statin. In addition, suboptimal LDL-C management during the follow-up period was observed even on statin treatment.The 3-year cumulative incidence of 15.3% for this endpoint was consistent with that seen in the placebo group of the FOURIER clinical trial 14.6%) , althoug.6% , altThere were a few noteworthy differences between the present cohort driven from AMC-HR and the FOURIER trial population. Firstly, there was a higher prevalence of IS and a lower prevalence of MI in the present cohort compared with FOURIER. It is well-known that Asians have a higher prevalence/incidence of IS than MI , 18. Of Management of LDL-C levels is important for the prevention of ASCVD; however, underutilization of lipid-lowering treatment and failure to intensify treatment is common, even for patients at high cardiovascular risk –26. MeasSeveral limitations should be noted. The first of these was inherent to the retrospective nature and observational design of the analyses. Confirmation of the results in a prospective study would be helpful. Second, although EMR data enabled reliable real-world estimates, findings from a single center cannot be generalized. Third, on analysis of risk factors for primary and secondary endpoints, cardiovascular protective medications such as aspirin, P2Y12 inhibitors, beta-blockers, or RAAS inhibitors were associated with recurrent events. These results may be due to inherent biases of retrospective analysis, but similar findings were also observed in other retrospective studies . It is rThis study in a routine practice setting in Korea found that very high-risk patients with clinically evident ASCVD were at substantial risk of further cardiovascular events within the subsequent 3 years. In addition, suboptimal LDL-C reduction, even on statin treatment, was observed. These findings may highlight the unmet need and clinical burden among very high-risk ASCVD patients treated with statin therapy and indicate the requirement for additional therapeutic options such as PCSK9 inhibitors.Supplementary file1 (DOCX 27 KB)Below is the link to the electronic supplementary material.